TNF-α Treatment of Blast-Induced Tinnitus

Summary

The purpose of this multi-site research study is to determine if Etanercept, compared to a placebo, significantly reduces the severity of tinnitus (ringing in the ears) associated with history of blast and/or noise exposure or associated with Traumatic Brain Injury (TBI) and/or concussion. Individuals who qualify will be randomized into one of two groups: The group receiving the medication Etanercept or the group receiving a saline solution placebo.

Timeline

Start

2022-07-01

Primary completion

2026-09

Completion

2026-09

Publications

• Background Meikle MB, Henry JA, Griest SE, Stewart BJ, Abrams HB, McArdle R, Myers PJ, Newman CW, Sandridge S, Turk DC, Folmer RL, Frederick EJ, House JW, Jacobson GP, Kinney SE, Martin WH, Nagler SM, Reich GE, Searchfield G, Sweetow R, Vernon JA. The tinnitus functional index: development of a new clinical measure for chronic, intrusive tinnitus. Ear Hear. 2012 Mar-Apr;33(2):153-76. doi: 10.1097/AUD.0b013e31822f67c0.
• Background Lew HL, Jerger JF, Guillory SB, Henry JA. Auditory dysfunction in traumatic brain injury. J Rehabil Res Dev. 2007;44(7):921-8. doi: 10.1682/jrrd.2007.09.0140.
• Background VBA. VA Annual Benefits Report: Fiscal Year 2012. In: VA US, ed. 810 Vermont Avenue N. W. , Washington, D.C., 20420: Veterans Benefits Administration, 2013:82.
• Background Hesser H, Westin V, Hayes SC, Andersson G. Clients' in-session acceptance and cognitive defusion behaviors in acceptance-based treatment of tinnitus distress. Behav Res Ther. 2009 Jun;47(6):523-8. doi: 10.1016/j.brat.2009.02.002. Epub 2009 Feb 10.
• Background Crocetti A, Forti S, Ambrosetti U, Bo LD. Questionnaires to evaluate anxiety and depressive levels in tinnitus patients. Otolaryngol Head Neck Surg. 2009 Mar;140(3):403-5. doi: 10.1016/j.otohns.2008.11.036.
• Background Hasson D, Theorell T, Wallen MB, Leineweber C, Canlon B. Stress and prevalence of hearing problems in the Swedish working population. BMC Public Health. 2011 Feb 23;11:130. doi: 10.1186/1471-2458-11-130.
• Background Hebert S, Fullum S, Carrier J. Polysomnographic and quantitative electroencephalographic correlates of subjective sleep complaints in chronic tinnitus. J Sleep Res. 2011 Mar;20(1 Pt 1):38-44. doi: 10.1111/j.1365-2869.2010.00860.x.
• Background Stevens C, Walker G, Boyer M, Gallagher M. Severe tinnitus and its effect on selective and divided attention. Int J Audiol. 2007 May;46(5):208-16. doi: 10.1080/14992020601102329.
• Background Rossiter S, Stevens C, Walker G. Tinnitus and its effect on working memory and attention. J Speech Lang Hear Res. 2006 Feb;49(1):150-60. doi: 10.1044/1092-4388(2006/012).
• Background Namas R, Ghuma A, Hermus L, Zamora R, Okonkwo DO, Billiar TR, Vodovotz Y. The acute inflammatory response in trauma / hemorrhage and traumatic brain injury: current state and emerging prospects. Libyan J Med. 2009 Sep 1;4(3):97-103. doi: 10.4176/090325.
• Background Eyre H, Baune BT. Neuroplastic changes in depression: a role for the immune system. Psychoneuroendocrinology. 2012 Sep;37(9):1397-416. doi: 10.1016/j.psyneuen.2012.03.019. Epub 2012 Apr 21.
• Background Beattie EC, Stellwagen D, Morishita W, Bresnahan JC, Ha BK, Von Zastrow M, Beattie MS, Malenka RC. Control of synaptic strength by glial TNFalpha. Science. 2002 Mar 22;295(5563):2282-5. doi: 10.1126/science.1067859.
• Background Steinmetz CC, Turrigiano GG. Tumor necrosis factor-alpha signaling maintains the ability of cortical synapses to express synaptic scaling. J Neurosci. 2010 Nov 3;30(44):14685-90. doi: 10.1523/JNEUROSCI.2210-10.2010.
• Background Stellwagen D, Malenka RC. Synaptic scaling mediated by glial TNF-alpha. Nature. 2006 Apr 20;440(7087):1054-9. doi: 10.1038/nature04671. Epub 2006 Mar 19.
• Background Schaette R, Kempter R. Computational models of neurophysiological correlates of tinnitus. Front Syst Neurosci. 2012 May 8;6:34. doi: 10.3389/fnsys.2012.00034. eCollection 2012.
• Background Yang S, Bao S. Homeostatic mechanisms and treatment of tinnitus. Restor Neurol Neurosci. 2013;31(2):99-108. doi: 10.3233/RNN-120248.
• Background Yang S, Weiner BD, Zhang LS, Cho SJ, Bao S. Homeostatic plasticity drives tinnitus perception in an animal model. Proc Natl Acad Sci U S A. 2011 Sep 6;108(36):14974-9. doi: 10.1073/pnas.1107998108. Epub 2011 Sep 6.
• Background Weinberg MS, Blake BL, McCown TJ. Opposing actions of hippocampus TNFalpha receptors on limbic seizure susceptibility. Exp Neurol. 2013 Sep;247:429-37. doi: 10.1016/j.expneurol.2013.01.011. Epub 2013 Jan 16.
• Background Kaneko M, Stellwagen D, Malenka RC, Stryker MP. Tumor necrosis factor-alpha mediates one component of competitive, experience-dependent plasticity in developing visual cortex. Neuron. 2008 Jun 12;58(5):673-80. doi: 10.1016/j.neuron.2008.04.023.
• Background Stellwagen D, Beattie EC, Seo JY, Malenka RC. Differential regulation of AMPA receptor and GABA receptor trafficking by tumor necrosis factor-alpha. J Neurosci. 2005 Mar 23;25(12):3219-28. doi: 10.1523/JNEUROSCI.4486-04.2005.
• Background Ogoshi F, Yin HZ, Kuppumbatti Y, Song B, Amindari S, Weiss JH. Tumor necrosis-factor-alpha (TNF-alpha) induces rapid insertion of Ca2+-permeable alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA)/kainate (Ca-A/K) channels in a subset of hippocampal pyramidal neurons. Exp Neurol. 2005 Jun;193(2):384-93. doi: 10.1016/j.expneurol.2004.12.026.
• Background Llano DA, Turner J, Caspary DM. Diminished cortical inhibition in an aging mouse model of chronic tinnitus. J Neurosci. 2012 Nov 14;32(46):16141-8. doi: 10.1523/JNEUROSCI.2499-12.2012.
• Background Middleton JW, Kiritani T, Pedersen C, Turner JG, Shepherd GM, Tzounopoulos T. Mice with behavioral evidence of tinnitus exhibit dorsal cochlear nucleus hyperactivity because of decreased GABAergic inhibition. Proc Natl Acad Sci U S A. 2011 May 3;108(18):7601-6. doi: 10.1073/pnas.1100223108. Epub 2011 Apr 18.
• Background Brozoski T, Odintsov B, Bauer C. Gamma-aminobutyric acid and glutamic acid levels in the auditory pathway of rats with chronic tinnitus: a direct determination using high resolution point-resolved proton magnetic resonance spectroscopy (H-MRS). Front Syst Neurosci. 2012 Feb 24;6:9. doi: 10.3389/fnsys.2012.00009. eCollection 2012.
• Background Isaacson JE, Moyer MT, Schuler HG, Blackall GF. Clinical associations between tinnitus and chronic pain. Otolaryngol Head Neck Surg. 2003 May;128(5):706-10. doi: 10.1016/S0194-59980300227-4.
• Background Moller AR. Similarities between chronic pain and tinnitus. Am J Otol. 1997 Sep;18(5):577-85.
• Background Tonndorf J. The analogy between tinnitus and pain: a suggestion for a physiological basis of chronic tinnitus. Hear Res. 1987;28(2-3):271-5. doi: 10.1016/0378-5955(87)90054-2.
• Background De Ridder D, Elgoyhen AB, Romo R, Langguth B. Phantom percepts: tinnitus and pain as persisting aversive memory networks. Proc Natl Acad Sci U S A. 2011 May 17;108(20):8075-80. doi: 10.1073/pnas.1018466108. Epub 2011 Apr 18.
• Background Ignatowski TA, Covey WC, Knight PR, Severin CM, Nickola TJ, Spengler RN. Brain-derived TNFalpha mediates neuropathic pain. Brain Res. 1999 Sep 11;841(1-2):70-7. doi: 10.1016/s0006-8993(99)01782-5.
• Background Covey WC, Ignatowski TA, Knight PR, Spengler RN. Brain-derived TNFalpha: involvement in neuroplastic changes implicated in the conscious perception of persistent pain. Brain Res. 2000 Mar 17;859(1):113-22. doi: 10.1016/s0006-8993(00)01965-x.
• Background Hess A, Axmann R, Rech J, Finzel S, Heindl C, Kreitz S, Sergeeva M, Saake M, Garcia M, Kollias G, Straub RH, Sporns O, Doerfler A, Brune K, Schett G. Blockade of TNF-alpha rapidly inhibits pain responses in the central nervous system. Proc Natl Acad Sci U S A. 2011 Mar 1;108(9):3731-6. doi: 10.1073/pnas.1011774108. Epub 2011 Jan 18.
• Background Widomski D, Fretland DJ, Gasiecki AF, Collins PW. The prostaglandin analogs, misoprostol and SC-46275, potently inhibit cytokine release from activated human monocytes. Immunopharmacol Immunotoxicol. 1997 May;19(2):165-74. doi: 10.3109/08923979709007656.
• Background Briner W, House J, O'Leary M. Synthetic prostaglandin E1 misoprostol as a treatment for tinnitus. Arch Otolaryngol Head Neck Surg. 1993 Jun;119(6):652-4. doi: 10.1001/archotol.1993.01880180068013.
• Background Akkuzu B, Yilmaz I, Cakmak O, Ozluoglu LN. Efficacy of misoprostol in the treatment of tinnitus in patients with diabetes and/or hypertension. Auris Nasus Larynx. 2004 Sep;31(3):226-32. doi: 10.1016/j.anl.2004.03.005.
• Background Page TH, Turner JJ, Brown AC, Timms EM, Inglis JJ, Brennan FM, Foxwell BM, Ray KP, Feldmann M. Nonsteroidal anti-inflammatory drugs increase TNF production in rheumatoid synovial membrane cultures and whole blood. J Immunol. 2010 Sep 15;185(6):3694-701. doi: 10.4049/jimmunol.1000906. Epub 2010 Aug 16.
• Background Hwang JH, Chen JC, Yang SY, Wang MF, Chan YC. Expression of tumor necrosis factor-alpha and interleukin-1beta genes in the cochlea and inferior colliculus in salicylate-induced tinnitus. J Neuroinflammation. 2011 Apr 9;8:30. doi: 10.1186/1742-2094-8-30.
• Background Wang HT, Luo B, Zhou KQ, Xu TL, Chen L. Sodium salicylate reduces inhibitory postsynaptic currents in neurons of rat auditory cortex. Hear Res. 2006 May;215(1-2):77-83. doi: 10.1016/j.heares.2006.03.004. Epub 2006 Apr 24.
• Background Satoh H, Firestein GS, Billings PB, Harris JP, Keithley EM. Tumor necrosis factor-alpha, an initiator, and etanercept, an inhibitor of cochlear inflammation. Laryngoscope. 2002 Sep;112(9):1627-34. doi: 10.1097/00005537-200209000-00019.
• Background Wang X, Truong T, Billings PB, Harris JP, Keithley EM. Blockage of immune-mediated inner ear damage by etanercept. Otol Neurotol. 2003 Jan;24(1):52-7. doi: 10.1097/00129492-200301000-00012.
• Background Matteson EL, Choi HK, Poe DS, Wise C, Lowe VJ, McDonald TJ, Rahman MU. Etanercept therapy for immune-mediated cochleovestibular disorders: a multi-center, open-label, pilot study. Arthritis Rheum. 2005 Jun 15;53(3):337-42. doi: 10.1002/art.21179.
• Background Rahman MU, Poe DS, Choi HK. Etanercept therapy for immune-mediated cochleovestibular disorders: preliminary results in a pilot study. Otol Neurotol. 2001 Sep;22(5):619-24. doi: 10.1097/00129492-200109000-00010.
• Background Van Wijk F, Staecker H, Keithley E, Lefebvre PP. Local perfusion of the tumor necrosis factor alpha blocker infliximab to the inner ear improves autoimmune neurosensory hearing loss. Audiol Neurootol. 2006;11(6):357-65. doi: 10.1159/000095897. Epub 2006 Sep 21.
• Background Scherer EQ, Yang J, Canis M, Reimann K, Ivanov K, Diehl CD, Backx PH, Wier WG, Strieth S, Wangemann P, Voigtlaender-Bolz J, Lidington D, Bolz SS. Tumor necrosis factor-alpha enhances microvascular tone and reduces blood flow in the cochlea via enhanced sphingosine-1-phosphate signaling. Stroke. 2010 Nov;41(11):2618-24. doi: 10.1161/STROKEAHA.110.593327. Epub 2010 Oct 7.
• Background Hiller W, Goebel G. A psychometric study of complaints in chronic tinnitus. J Psychosom Res. 1992 May;36(4):337-48. doi: 10.1016/0022-3999(92)90070-i.
• Background Falkenberg ES, Wie OB. Anxiety and depression in tinnitus patients: 5-year follow-up assessment after completion of habituation therapy. Int J Otolaryngol. 2012;2012:375460. doi: 10.1155/2012/375460. Epub 2012 Mar 28.
• Background Halford JB, Anderson SD. Anxiety and depression in tinnitus sufferers. J Psychosom Res. 1991;35(4-5):383-90. doi: 10.1016/0022-3999(91)90033-k.
• Background Harrop-Griffiths J, Katon W, Dobie R, Sakai C, Russo J. Chronic tinnitus: association with psychiatric diagnoses. J Psychosom Res. 1987;31(5):613-21. doi: 10.1016/0022-3999(87)90040-7.
• Background Henry JL, Wilson PH. Coping with Tinnitus: Two Studies of Psychological and Audiological Characteristics of Patients with High and Low Tinnitus-Related Distress. Int Tinnitus J. 1995;1(2):85-92.
• Background Seydel C, Haupt H, Olze H, Szczepek AJ, Mazurek B. Gender and chronic tinnitus: differences in tinnitus-related distress depend on age and duration of tinnitus. Ear Hear. 2013 Sep;34(5):661-72. doi: 10.1097/AUD.0b013e31828149f2.
• Background Tyler RS, Gogel SA, Gehringer AK. Tinnitus activities treatment. Prog Brain Res. 2007;166:425-34. doi: 10.1016/S0079-6123(07)66041-5.
• Background Tyler R, Ji H, Perreau A, Witt S, Noble W, Coelho C. Development and validation of the tinnitus primary function questionnaire. Am J Audiol. 2014 Sep;23(3):260-72. doi: 10.1044/2014_AJA-13-0014.
• Background Scott B, Lindberg P, Melin L, Lyttkens L. Predictors of tinnitus discomfort, adaptation and subjective loudness. Br J Audiol. 1990 Feb;24(1):51-62. doi: 10.3109/03005369009077842.
• Background Herbert TB, Cohen S. Stress and immunity in humans: a meta-analytic review. Psychosom Med. 1993 Jul-Aug;55(4):364-79. doi: 10.1097/00006842-199307000-00004.
• Background Kiecolt-Glaser JK, Marucha PT, Malarkey WB, Mercado AM, Glaser R. Slowing of wound healing by psychological stress. Lancet. 1995 Nov 4;346(8984):1194-6. doi: 10.1016/s0140-6736(95)92899-5.
• Background Huerta PT, Kowal C, DeGiorgio LA, Volpe BT, Diamond B. Immunity and behavior: antibodies alter emotion. Proc Natl Acad Sci U S A. 2006 Jan 17;103(3):678-83. doi: 10.1073/pnas.0510055103. Epub 2006 Jan 4.
• Background Andrews JA, Neises KD. Cells, biomarkers, and post-traumatic stress disorder: evidence for peripheral involvement in a central disease. J Neurochem. 2012 Jan;120(1):26-36. doi: 10.1111/j.1471-4159.2011.07545.x. Epub 2011 Nov 17.
• Background Hansel A, Hong S, Camara RJ, von Kanel R. Inflammation as a psychophysiological biomarker in chronic psychosocial stress. Neurosci Biobehav Rev. 2010 Sep;35(1):115-21. doi: 10.1016/j.neubiorev.2009.12.012. Epub 2009 Dec 22.
• Background Steptoe A, Hamer M, Chida Y. The effects of acute psychological stress on circulating inflammatory factors in humans: a review and meta-analysis. Brain Behav Immun. 2007 Oct;21(7):901-12. doi: 10.1016/j.bbi.2007.03.011. Epub 2007 May 1.
• Background Bob P, Raboch J, Maes M, Susta M, Pavlat J, Jasova D, Vevera J, Uhrova J, Benakova H, Zima T. Depression, traumatic stress and interleukin-6. J Affect Disord. 2010 Jan;120(1-3):231-4. doi: 10.1016/j.jad.2009.03.017.
• Background Szczepek AJ, Haupt H, Klapp BF, Olze H, Mazurek B. Biological correlates of tinnitus-related distress: an exploratory study. Hear Res. 2014 Dec;318:23-30. doi: 10.1016/j.heares.2014.10.007. Epub 2014 Oct 28.
• Background Weber C, Arck P, Mazurek B, Klapp BF. Impact of a relaxation training on psychometric and immunologic parameters in tinnitus sufferers. J Psychosom Res. 2002 Jan;52(1):29-33. doi: 10.1016/s0022-3999(01)00281-1.
• Background Arck PC, Rose M, Hertwig K, Hagen E, Hildebrandt M, Klapp BF. Stress and immune mediators in miscarriage. Hum Reprod. 2001 Jul;16(7):1505-11. doi: 10.1093/humrep/16.7.1505.
• Background Folstein MF, Folstein SE, McHugh PR. "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975 Nov;12(3):189-98. doi: 10.1016/0022-3956(75)90026-6. No abstract available.
• Background Andersson G. Tinnitus loudness matchings in relation to annoyance and grading of severity. Auris Nasus Larynx. 2003 May;30(2):129-33. doi: 10.1016/s0385-8146(03)00008-7.
• Background Andersson G, Lyttkens L, Larsen HC. Distinguishing levels of tinnitus distress. Clin Otolaryngol Allied Sci. 1999 Sep;24(5):404-10. doi: 10.1046/j.1365-2273.1999.00278.x.

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Indications